title: Calcitonin gene-related peptide-mediated enhancement of purinergic neuron/glia communication by the algogenic factor bradykinin in mouse trigeminal ganglia from wild-type and R192Q Cav2.1 Knock-in mice: implications for basic mechanisms of migraine pain.
abstract: Within the trigeminal ganglion, crosstalk between neurons and satellite glial cells (SGCs) contributes to neuronal sensitization and transduction of painful stimuli, including migraine pain, at least partly through activation of purinergic receptor mechanisms. We previously showed that the algogenic mediator bradykinin (BK) potentiates purinergic P2Y receptors on SGCs in primary trigeminal cultures. Our present study investigated the molecular basis of this effect in wild-type (WT) mice and Ca(V)2.1 α1 R192Q mutant knock-in (KI) mice expressing a human mutation causing familial hemiplegic migraine type 1. Single-cell calcium imaging of WT cultures revealed functional BK receptors in neurons only, suggesting a paracrine action by BK to release a soluble mediator responsible for its effects on SGCs. We identified this mediator as the neuropeptide calcitonin gene-related peptide (CGRP), whose levels were markedly increased by BK, while the CGRP antagonist CGRP(8-37) and the anti-migraine drug sumatriptan inhibited BK actions. Unlike CGRP, BK was ineffective in neuron-free SGC cultures, confirming the CGRP neuronal source. P2Y receptor potentiation induced by CGRP in SGCs was mediated via activation of the extracellular signal-regulated kinase 1/2 pathways, and after exposure to CGRP, a significant release of several cytokines was detected. Interestingly, both basal and BK-stimulated CGRP release was higher in KI mouse cultures, where BK significantly upregulated the number of SGCs showing functional UTP-sensitive P2Y receptors. Our findings suggest that P2Y receptors on glial cells might be considered as novel players in the cellular processes underlying migraine pathophysiology and might represent new targets for the development of innovative therapeutic agents against migraine pain.
authors.affiliation: Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ceruti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Villa
authors.forename: Marta
authors.initials: M
authors.lastname: Fumagalli
authors.forename: Laura
authors.initials: L
authors.lastname: Colombo
authors.forename: Giulia
authors.initials: G
authors.lastname: Magni
authors.forename: Matteo
authors.initials: M
authors.lastname: Zanardelli
authors.forename: Elsa
authors.initials: E
authors.lastname: Fabbretti
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.forename: Andrea
authors.initials: A
authors.lastname: Nistri
authors.forename: Maria P
authors.initials: MP
authors.lastname: Abbracchio
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001920:Bradykinin / Q000378:metabolism* / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008881:Migraine Disorders / Q000209:etiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D001920:Bradykinin; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium; D020864:Calcium Channels, N-Type; D048052:Mitogen-Activated Protein Kinase 3; D058470:Receptors, Purinergic P2Y